Breast Cancer Research and Treatment, 3, 365—372 (1983)
`© 1983, Martinus Nijhoff Publishers, Boston. Printed in the Netherlands
`
`Report
`
`Chemoendocrine therapy vs chemotherapy alone for advanced breast cancer
`in postmenopausal women: preliminary report of a randomized study
`
`Cancer and Leukemia Group B Study 8081
`
`Carl G. Kardinal“, Michael C. Perry", Vivian Weinberg”, William Wood”, Sandra Ginsberge, and Robert N.
`Rajuf, for the Cancer and Leukemia Group B
`“Ochsner Clinic and Alton Ochsner Medical Foundation, New Orleans, Louisiana, USA," b University of
`Missouri, Columbia, Missouri, USA; “CALGB Statistical Office, Brookline, Massachusetts, USA; dMassa—
`cliusetts General Hospital, Boston, Massachusetts, USA; 6 State University of New York, Syracuse, New York,
`USA;fEllis Fischel State Cancer Hospital, Columbia, Missouri, USA
`
`Keywords: advanced breast cancer, CAF, chemoendocrine therapy, chemotherapy, tamoxifen
`
`Summary
`
`From January 1980 to August 1982 the Cancer and Leukemia Group B conducted a prospective randomized
`trial comparing chemoendocrine therapy with T-CAF (cyclophosphamide, adriamycin, and 5~f1uor0uracil
`plus tamoxifen) to CAF alone in postmenopausal women with advanced breast cancer. The patients were
`stratified by estrogen receptor (ER) status into three groups: ER-negative, ER—positive, ER-unknown. They
`were also stratified by dominant site of metastatic disease: visceral and other (osseous and/or soft tissue).
`A total of 246 eligible patients were enrolled in the study; 232 were evaluable and constitute the basis for this
`report. The study revealed that there was no difference in overall response frequency or response duration
`between T-CAF and CAF; there was no difference in response between T-CAF and CAF in ER-positive or in
`ER—negative patients; and there was no difference in response between T-CAF and CAF by dominant site of
`metastatic disease. The expected advantage of T-CAF over CAF, especially for ER—positive patients, was not
`observed.
`
`Introduction
`
`Metastatic breast cancer is responsive to a variety
`of cytotoxic drugs with differing mechanisms of
`action (1). This makes breast cancer the prototype
`solid tumor for the study of combination chemo—
`therapy. Greenspan (2) introduced the use of com-
`bination chemotherapy in advanced breast cancer
`almost twenty years ago. This was modified by
`Cooper (3), and then further modified following the
`introduction of adriamycin (1). Multiple attempts
`have been made to combine and recombine the
`
`various active agents into 2-drug, 3-drug, 4-drug,
`5-drug, and even 6-drug combinations. However,
`the results have plateaued. It appears that by using
`currently available drugs, an objective response rate
`of 50% to 65% can be obtained, with about 10% to
`15% of the responses being complete. The median
`response durations are from 9 to 16 months.
`It has been recognized for many years that 20%
`to 25% of unselected breast cancers are hormonally
`responsive (4). By restricting endocrine manipula-
`
`tion to tumors containing estrogen receptor (ER)
`protein, the response rate can be increased to 55%.
`
`Address for reprints: Carl G. Kardinal, MD, Ochsner Clinic, 1514 Jefferson Highway, New Orleans, LA 70121, USA.
`
`Genentech 2072
`
`Celltrion v. Genentech
`
`|PR2017-01122
`
`Genentech 2072
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`366
`
`CG Kara’inal et al.
`
`Again most of these responses are incomplete and
`of relatively short duration.
`Greene and Jensen (5), using fluorescent staining
`techniques with monoclonal antibody for estrogen
`receptor, have recently noted that many breast
`cancers are heterogeneous in terms of their ER
`content. That is, breast cancers are composed of
`
`both ER—positive cells as well as ER-negative cells.
`A tumor’s ER positivity or ER negativity appears
`to depend upon the relative concentration of recep-
`tor activity in the various cells present. Using
`immunocytochemical techniques, Mercer et al. (6)
`have demonstrated that 71°/0 of human breast
`cancers are heterogeneous for estradiol binding.
`Since the results of treatment of advanced breast
`
`cancer have plateaued, new approaches to therapy
`are needed. Based upon the observation that the
`majority of breast cancers are heterogeneous in
`terms of ER content (5, 6), and the recognition that
`endocrine therapy and cytotoxic chemotherapy have
`different mechanisms of action,
`the Cancer and
`
`Leukemia Group B (CALGB) performed a study
`evaluating the relative effectiveness of chemoendo—
`crine therapy as compared to chemotherapy alone
`in postmenopausal women with advanced breast
`cancer. Although chemoendocrine therapy had a
`theoretical advantage over chemotherapy alone, it
`was felt that a prospectively randomized controlled
`study was necessary to truly answer the question.
`Also, a controlled study was felt to be necessary
`since the endocrine therapy could compromise the
`effectiveness of the cytotoxic drugs by altering the
`
`cycling characteristics of the tumor cells. This con-
`stitutes the report of the first major data analysis of
`CALGB Study 8081.
`
`Methods
`
`Cancer and Leukemia Group B Study 8081, a
`randomized trial comparing chemoendocrine thera-
`
`py with T-CAF (cyclophosphamide, adriamycin,
`5-flu0rouracil plus tamoxifen)
`to chemotherapy
`alone (CAF) in postmenopausal women with ad-
`vanced breast cancer, was open to patient entry
`from January 1980 to August 1982. Postmeno-
`pausal women with histologically documented carci—
`
`noma of the breast were eligible if they had measur-
`able metastatic, locally recurrent, or surgically in—
`curable (stage IV) disease. Only patients with their
`first recurrence were eligible. Patients were not
`eligible if they had a performance status of greater
`than 3, or a second primary malignant neoplasm or
`a malignant neoplasm of the breast other than
`carcinoma. A history of recent myocardial infarc-
`tion, congestive heart failure, or documented angi-
`na also rendered the patient ineligible. Patients who
`had completed adjuvant chemotherapy greater than
`six months prior to entry were eligible provided it
`was their first documented recurrence. Prior thera—
`
`py with tamoxifen rendered the patient ineligible.
`Informed consent was obtained from all patients.
`
`Stratifz'cations
`
`The patients were stratified on the basis of ER
`status, dominant site of metastatic disease, and by
`no prior therapy versus prior adjuvant chemothera-
`py (Table 1). The estrogen receptor assays were
`quality controlled by internal monitoring utilizing
`reference powders provided by James Wittliff, PhD,
`
`of the University of Louisville. Detailed results of
`the quality control program will be the subject of a
`subsequent publication. There was good agreement
`for all
`laboratories analyzing reference powders
`which were negative, and only one of fourteen
`laboratories tested reported a negative result on an
`
`ER-positive reference powder. Patients were strati-
`fied into three groups on the basis of ER: ER-
`positive 27 femtomoles/mg protein; ER-negative
`
`Table 1. Stratifications.
`
`l.
`
`2.
`
`3.
`
`Estrogen receptor (ER) status
`A. ER-negative
`<7 femtomoles/mg protein
`B. ER-positive
`27 femtomoles/mg protein
`C. ER-unknown
`_ test not performed
`Dominant site ofmetastatic disease
`A. Visceral
`B. Osseous
`C. Soft tissue
`
`Prior therapy
`A. No prior therapy
`B. Prior adjuvant chemotherapy
`
`

`

`< 7 femtomoles/mg protein; ER-unknown (test not
`performed).
`
`The cut-off value of 7 femtomoles/mg was select~
`ed based upon the data of Hilf et a1. (7). Stratifica—
`tion by site of metastatic disease was into two
`
`groups: visceral dominant or other (osseous and/or
`soft
`tissue). An attempt was made to separate
`osseous and soft tissue dominant during the data
`analysis. This did result
`in a stratification im—
`balance which will be pointed out.
`
`Randomization
`
`Based upon the appropriate stratifications, patients
`were randomized to receive CAF chemotherapy
`alone (cyclophosphamide, adriamycin, 5-fluoro-
`uracil) or T—CAF chemoendocrine therapy (CAF
`+ tamoxifen). The schema for CALGB Study 8081
`is illustrated in Fig. 1.
`
`Treatment schedule
`
`Patients randomized to receive T-CAF received the
`
`tamoxifen continuously in a dose of 10 mg twice
`daily. The chemotherapy was the same in each
`
`
`
`Chemoendocrine therapy vs chemotherapy
`
`367
`
`treatment arm and was given in intermittent cycles
`over a 28—day period with 14 days of cytotoxic drug
`administration followed by a 14-day rest as follows
`(see Fig. 1): cyclophosphamide 100 mg/mZ/day p.o.
`days 1—14; adriamycin 25 mg/m2 i.V. days 1 and 8;
`and 5-fluorouracil 500 mg/m2 i.v. days 1 and 8.
`Treatment cycles were repeated on day 29, 57, 85,
`etc. After a total cumulative dose of adriamycin of
`450 mg/m2 had been administered, methotrexate
`
`was substituted. The methotrexate dose was 40 mg/
`In2 i.v. on days 1 and 8 unless the patient was over
`age 60 in which case it was reduced to 30 mg/m2.
`
`Response criteria
`
`A complete response (CR) was defined as complete
`disappearance of all signs and symptoms attribut-
`able to the tumor including the disappearance of all
`measurable lesions for at least one month and the
`
`appearance of no new lesions. For osseous disease a
`
`CR required recalcification of all osteolytic lesions.
`A partial response (PR) was defined as greater than
`50% reduction in the sum of the products of the two
`largest perpendicular diameters of all measured
`lesions with no deterioration in performance status,
`
`Repeat cycle every
`28 days until relapse
`
`D
`
`I]
`
`Repeat cycle every
`28 days until relapse
`
`
`1
`3
`6
`43
`50
`
`Tamoxifen 10mg., p.o., b.i.d. :1 Adriamycin 25mg./M2 i.v. days
`total dose continuously
`1&8 of each cycle (Max.450mg. M2)
`Cyclophosphamide
`5-Fluorouracil 500mg./M2 i.v. days
`1&8 of each cycle
`100mg./M2/day x 14 p.0.
`Activated February 1,1980
`Closed
`August 1.1982
`
`
`
`Fig. 1. Schema of Cancer and Leukemia Group B Study 8081. Treatment of metastatic breast cancer in postmenopausal women.
`
`

`

`368
`
`CG Kardinal et al.
`
`and without the appearance of any new lesions.
`There was no provision in the study for ER-
`positive or ER-unknown patients randomized to
`CAF alone who did not respond, or who responded
`and then failed, to automatically receive tamoxifen
`alone as secondary treatment.
`
`Statistical aspects
`
`This interim analysis was performed primarily using
`the chi—square test for contingency tables and Bres—
`low’s modification of the Kruskal—Wallis test. Multi-
`
`variate analyses using Cox’s linear logistic model
`were also used to assess the importance of prog—
`nostic variables on response.
`
`Results
`
`A total of 246 eligible patients were enrolled in the
`study. Of these, 232 were evaluable for response.
`Fourteen caseswere too early to evaluate. An
`additional 21 cases were disqualified (11 T-CAF
`and 10 CAF) because of a major protocol Violation,
`inadequate records or improper randomization. The
`comparability of the treatment groups is outlined in
`Table 2. The two treatment groups are comparable
`
`there was an
`i.e.,
`with one notable exception,
`imbalance in the stratification for dominant site of
`
`disease (p = 0.02). The reason for this imbalance is
`explained in the section entitled Stratifications. This
`imbalance probably accounts for the difference in
`response between T-CAF and CAF in the ER-
`unknown group. The ER—unknown group treated
`with T-CAF contained twice as many visceral domi—
`nant patients as the ER-unknown group treated
`with CAF.
`
`The overall response frequency for all patients is
`outlined in Table 3. There is no difference in overall
`
`response rate (CR + PR) between T-CAF (56%)
`and CAF (51%). The overall response durations are
`outlined in Table 4. Response duration is defined as
`the period that a patient achieved a documented
`CR or PR to the time of documented disease
`
`progression. Since this is the first major data
`analysis for this study, the maximum follow—up is
`only 22 months. However, at this time, there is no
`difference in projected median response duration
`for T—CAF (17.3 months) as compared to CAF
`(14.6 months). Also there is no difference in the
`percent of responders remaining in remission at 12
`months for the T-CAF-treated group (59%) com—
`pared to the CAF group (56%).
`When the data were analyzed for response by ER
`
`Table 2. Comparability of treatment groups.
`
`Table 3. Overall frequency of response.
`
`Total eligible
`Number evaluable
`Dominant site of metastases
`Visceral
`Osseous
`Soft tissue
`Estrogen receptor status
`ER-negative
`ER-positive
`ER-unknown
`Prior therapy
`Adjuvant chemotherapy
`No prior therapy
`Performance status
`0—1
`M
`
`T-CAF
`
`CAF
`
`120
`116
`
`71%
`17%
`12%
`
`33%
`29%
`38%
`
`11%
`89%
`
`71%
`29%
`
`126
`116
`
`59%
`32%
`9%
`
`32.5%
`35%
`32.5%
`
`14%
`86%
`
`79%
`21%
`
`Therapy
`
`T—CAF
`CAF
`
`N
`
`1 l6
`1 l6
`
`CR
`
`PR
`
`%CR + PR
`
`18(15.5%)
`16(14%)
`
`47(40.5%)
`430.7%)
`
`56
`51
`
`N = number of evaluable cases; CR 2 complete response;
`PR = partial response.
`
`Table 4. Duration of response 4 preliminary data (follow-up
`up to 22 months).
`
`Projected
`median
`
`% responders in
`remission at
`12 months
`
`T-CAF
`CAF
`
`17.3 months
`14.6 months
`
`59%
`56%
`
`

`

`status, there were also no differences in response
`between T-CAF and CAF for either ER-negative or
`ER-positive patients (Table 5). The responses in the
`ER-positive patients were identical whether they
`were treated with T-CAF (47%) or with CAF
`(50%). Response in the ER—negative patients was
`greater with CAF alone (70%) than for T-CAF
`(54%), but this did not achieve statistical signifi-
`cance (p = 0.14). The difference in response observed
`for ER-unknown patients treated with T-CAF (65%)
`vs CAF (33%) seems to be due to a decreased
`response to CAF rather than an increased response
`to T—CAF. This difference is difficult to reconcile.
`
`Perhaps the stratification imbalance for dominant
`site of disease may account for it at least partially.
`Obviously, ER-unknown patients must consist of
`ER-positive and ER-negative cases and there were
`no differences in response in the latter two groups.
`A secondary objective of this study was to
`evaluate differences in responses to CAF chemo-
`therapy in ER-positive patients as compared to ER-
`negative. These data are also displayed in Table 5.
`There appears to be an advantage in response to
`CAF for ER-negative patients (70% as compared
`to 50% for ER-positive). Despite the fact that there
`is a 20% difference, the data do not achieve statisti-
`cal significance (p = 0.07). These data will be care-
`
`Chemoena’ocrine therapy vs chemotherapy
`
`369
`
`fully re-evaluated in subsequent analyses of this
`study. From a theoretical point of view, one would
`anticipate a higher response rate to cytotoxic chemo-
`therapy in ER-negative tumors since they tend to
`have a higher thymidine labeling index and growth
`rate as well as a shorter disease-free interval (8).
`Response by dominant site of metastatic disease is
`outlined in Table 6. There are no differences in
`
`response between T-CAF and CAF in visceral
`dominant, osseous dominant, or soft tissue domi-
`nant metastatic disease.
`
`Lastly, the data were analyzed in terms of no
`prior chemotherapy versus prior adjuvant chemo-
`therapy completed greater than six months prior to
`protocol entry (Table 7). This was restricted to
`those patients who would be receiving their first
`systemic treatment for metastatic disease. Although
`the protocol was open to patients who had received
`any type of adjuvant chemotherapy, almost all of
`the previously treated group had received adjuvant
`CMF (cyclophosphamide, methotrexate, 5-flu0ro-
`uracil). No patient had received adjuvant hormonal
`therapy. Most of these had been treated in accor-
`dance with a previous CALGB protocol evaluating
`adjuvant chemotherapy with CMF vs CMF + MER
`vs CMFVP (vincristine, prednisone). There was no
`difference between T-CAF and CAF in those pa-
`
`Table 5. Response by ER status.
`
`
`T-CAF
`
`CAF
`
`P
`
`(CR + PR/total)
`(CR + PR/total)
`
`ER-negative
`9 + 12/39 = 54%
`0.14
`4 + 22/37 = 700/,"
`ER-positive
`2 + 14/34 = 47%
`0.80
`7 + 13/40 = 50%“
`ER-unknown
`7 + 21/43 = 65%
`0.004
`5 + 8/39 = 33%,
`_.—__—_—___—_—__—_—____——
`
`a p = 0.07
`
`Table 6. Response by dominant site of metastatic disease.
`T-CAF
`
`CAF
`
`p
`
`(CR + PR/total)
`(CR + PR/total)
`
`0.95
`9 + 26/69 = 51%
`15 + 27/82 = 51%
`Visceral
`1 + 10/20 = 55%
`Osseous
`0.72
`4 + 15/38 = 50%
`2 + 10/14 = 86%
`Soft tissue
`
`3+ 2/9=56% 0.11
`
`

`

`370
`
`CG Kardinal el al.
`
`Table 7. Response by prior adjuvant chemotherapy (adjuvant chemotherapy completed greater than six months prior to protocol entry).
`
`T-CAF
`
`
`
`CAF p
`
`(CR + PR/total)
`
`(CR + PR/total)
`
`17 + 43/103 = 58%
`
`13 + 38/99 = 51%
`
`0.34
`
`1+ 4/13=3s%
`
`
`
`3 + 5/17 = 47% 0.26
`
`No prior chemotherapy
`Prior adjuvant
`chemotherapy
`
`tients who had no prior chemotherapy nor was
`there difference between T—CAF and CAF in those
`
`patients who had prior adjuvant chemotherapy. But
`what is of more interest is that those patients who
`received prior adjuvant chemotherapy responded to
`CAF with the same frequency as those who had no
`prior chemotherapy (47% vs 51%).
`The toxicity observed during this study is what
`would have been expected for CAF alone, i.e., mild
`to moderate myelosuppression, mild to moderate
`nausea and vomiting, and alopecia. None of the
`patients developed severe or life—threatening compli—
`cations. There was no additional toxicity observed
`
`in those patients treated with tamoxifen. Specifi—
`cally, none of the patients treated with tamoxifen
`were observed to have developed hypercalcemia or
`a tumor flare.
`
`Discussion
`
`The expected theoretical advantage for T-CAF
`chemoendocrine therapy over standard CAF chemo-
`
`therapy alone was not observed even in the subset
`of patients who were ER-positive. This is in con—
`trast to the data of Cocconi et a1. (9) who conducted
`a similar but smaller study, evaluating CMF :1;
`tamoxifen in 133 postmenopausal women with
`metastatic breast cancer. In their series the group
`treated with tamoxifen + CMF had a greater re-
`
`sponse rate, but response duration and survival
`were equivalent. The results reported by Mouridsen
`et al. (10) also evaluating CMF j: tamoxifen were
`similar to those of Coconni et al. These two studies
`
`utilized the cycle active drug methotrexate rather
`than the more active but cycle nonspecific drug
`adriamycin. The differences observed in response
`
`using CMF + tamoxifen may have been masked in
`our study by a kinetic effect of the adriamycin.
`There are two reported series evaluating chemo-
`endocrine therapy utilizing an adriamycin—contain—
`ing drug combination with tamoxifen. The first of
`these was reported by Ahmann et al. (11). They
`treated a group of 65 evaluable patients with
`adriamycin and cyclophosphamide (AC) plus tam-
`oxifen and compared this to a historical control
`group of patients treated with AC alone between
`1973 and 1975. They concluded that AC plus
`
`tamoxifen was superior to AC alone. The other
`reported series utilizing an adriamycin combination
`is that of Tormey et al. (12). They reported a group
`of 135 patients with advanced breast cancer who
`had been previously treated with chemotherapy
`who were randomized to adriamycin plus dibromo-
`dulcitol j: tamoxifen. They did note an advantage
`to the tamoxifen-treated group. However, the re-
`
`sponse to chemotherapy alone in their series was
`quite low, probably reflecting the fact
`that
`the
`patients had been heavily previously treated.
`Perhaps one of the most interesting observations
`of the present study is that patients who received
`prior adjuvant chemotherapy completed more than
`six months prior to protocol entry, responded well
`to CAF chemotherapy. This is despite the fact that
`almost all of this group of patients had received
`prior CMF,
`i.e., they had previously received at
`least two of the agents. Moreover, the response rate
`of these patients to CAF was essentially the same as
`those patients who had not been previously treated
`(47% vs 51%). This response rate is markedly better
`than the 20% to 25% expected for adriamycin alone
`in previously treated patients (1). This implies that
`patients who fail after completion of adjuvant
`chemotherapy are not inherently resistant to further
`
`

`

`treatment with similar chemotherapeutic regimens.
`The rationale for the combined use of endocrine
`
`therapy and chemotherapy appears sound especial—
`ly since breast cancers have been shown to be
`heterogeneous tumors composed of ER-positive
`and ER—negative cells (5, 6). According to Osborne
`(13), a simple additive effect on tumor cell kill
`would be observed only if the endocrine therapy
`and chemotherapy did not interact with each other
`biochemically, biologically, or pharmacologically.
`The effects of hormonal manipulation on breast
`cancer cell kinetics suggest that traditional endo—
`crine therapy may serve to antagonize the effects of
`certain cytotoxic drugs by blocking tumor cells in
`an unfavorable position in the cell cycle. With
`tamoxifen a progressively larger fraction of tumor
`cells is found accumulating in the G1 phase of the
`cell cycle (13).
`It must therefore be concluded that the addition
`
`of tamoxifen to CAF chemotherapy offers no
`therapeutic advantage regardless of estrogen recep-
`tor status. It must also be concluded that simul—
`
`taneous chemoendocrine therapy utilizing cytotoxic
`drugs plus tamoxifen cannot be recommended.
`
`References
`
`1. Kardinal CG: Chemotherapy. In WL Donegan, JS Spratt
`(eds). Cancer of the Breast. Saunders, Philadelphia, 1979, pp
`405447
`
`2. Greenspan EM, Fieber M, Lesnick G, Edelman S: Response
`of advanced breast carcinoma to the combination of the
`
`antimetabolite, methotrexate, and the alkylating agent,
`thiotepa. .1 Mt Sinai Hosp 30:246—267, 1963
`
`Chemoendocrine lherapy vs chemotherapy
`
`.37]
`
`. Cooper R: Combination chemotherapy in hormone resis-
`tant breast cancer (Abstract). Proc Am Assoc Cancer Res
`10:15, 1969
`Kardinal CG, Donegan WL: Endocrine and hormonal
`therapy. In WL Donegan, JS Spratt (eds). Cancer of the
`Breast. Saunders, Philadelphia, 1979, pp 361—404
`. Greene GL, Jensen EV: The use of monoclonal antibodies in
`estrogen receptor assays (Abstract). Proc 13th Int Cancer
`Congress, Seattle, Washington, September 8—15, 1982, p 573
`Mercer WD, Lippman ME, Wahl TM, Carlson CA, Wahl
`DA, Legotte D, Teague P0: The use of immunocytochemi-
`cal
`techniques for the detection of steroid hormones in
`breast cancer cells. Cancer 46:2859—2868, 1980
`Hilf R, Wittliff JL, Rector WD, Savlov ED, Hall TC,
`Orlando RA: Studies on certain cytoplasmic enzymes and
`specific estrogen receptors in human breast cancer and in
`nonmalignant diseases of the breast. Cancer Res 33220547
`2062, 1973
`. Lippman ME, Allegra JC: Quantitative estrogen receptor
`analyses: the response to endocrine and cytotoxic chemo—
`therapy in human breast cancer and the disease—free inter—
`val. Cancer 461282942834, 1980
`Cocconi G, DeLisa V, Mori P, Malacarne P, Amadori D,
`Giovanelli E: Chemotherapy versus combination of chemo-
`therapy and endocrine therapy in advanced breast cancer: a
`randomized study. Cancer 51:581—588, 1983
`Mouridsen HT, Palshof T, Engelsman E, Sylvester R: CMF
`versus CMF plus tamoxifen in advanced breast cancer in
`postmenopausaliwomen. An EORTC trial. In HT Mourid-
`sen, T Palshof (eds). Breast Cancer 7 Experimental and
`Clinical Aspects. Pergamon Press, Oxford, 1980, pp 119~123
`Ahmann FR, Jones SE, Moon TE, Davis SL, Salmon SE:
`Improved survival of patients with advanced breast cancer
`treated with adriamycin-cyclophosphamide plus tamoxifen
`(TAC) (Abstract). Proc AACR/ASCO 22:148, 1981
`Tormey DC, Falkson HC, Falkson G, Voelkel J, Crowley J,
`Davis TE: Dibromoducitol and adriamycin :L- tamoxifen in
`advanced breast cancer. Am J Clin Oncol 53339, 1982
`Osborne CK: Combined chemo—hormonal therapy in breast
`cancer: a hypothesis. Breast Cancer Res Treat 1:1217123,
`1981
`
`12.
`
`13.
`
`10.
`
`11.
`
`